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Letter to the Editor
Clinical Microbiology
Correlation of Aminoglycoside Consumption and Amikacin- or Gentamicin-Resistant Pseudomonas aeruginosa in Long-Term Nationwide Analysis: Is Antibiotic Cycling an Effective Policy for Reducing Antimicrobial Resistance?
Young Ah Kim, M.D.1, Yoon Soo Park, M.D.2, Taemi Youk, M.D.3, Hyukmin Lee, M.D.4, and Kyungwon Lee, M.D.4
Department of Laboratory Medicine1, National Health Insurance Service Ilsan Hospital, Goyang; Department of Internal Medicine2, National Health Insurance Service Ilsan Hospital, Goyang; Department of Statistics3, Korea University, Seoul; Department of Laboratory Medicine and Research Institute of Bacterial Resistance4, Yonsei University College of Medicine, Seoul, Korea
Dear Editor,
Bacteria continuously develop, acquire, and spread numerous resistance patterns shortly after new antibiotics reach the mar- ket. Recently, carbapenem-resistant Enterobacteriaceae (CRE) and colistin-resistant Acinetobacter baumannii are emerging, which may lead us into the pre-antibiotic era. Pipelines of new antibiotics are becoming thinner and thinner across all thera- peutic areas due to difficulties in innovation and challenges of regulatory hurdles. Under such a situation, maintaining antibi- otic effectiveness in the long term requires not only innovation to develop new antibiotics, but also conservation of the effective- ness of existing antibiotics.
Antibiotic cycling or rotation consists of the sequential use of antibiotics not sharing a common mechanism of resistance, which could be considered as a strategy for conservation. Aminoglyco- side consumption has continuously decreased during the recent five years [1]. The rates of amikacin or gentamicin-resistant Kleb- siella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter spp. also showed declining trends according to data from the
Korean Nationwide Surveillance of Antimicrobial Resistance (KO- NSAR) program [2]. The decreasing prevalence of amikacin and tobramycin resistance in some Gram-negative bacteria was associated with decreased consumption levels of these antimi- crobial agents in a single-center study [3]. Aminoglycosides, ex- cept amikacin, can be considered as old drugs; however, they remain key roles in the treatment of infections. They also pos- sess potent bactericidal activity against some CRE [4].
We investigated the correlation of aminoglycoside consump- tion and its resistance in P. aeruginosa using a nationwide sur- veillance and antibiotic prescription database to provide back- ground data on the effectiveness of antibiotic cycling at the na- tional level. Data on antibiotic usage in Korea from 2002 to 2013 were acquired from the database of the National Health Insur- ance Service-National Sample Cohort (NHIS-NSC), a popula- tion-based cohort established to provide public health research- ers and policy makers with representative information regarding the utilization of health insurance and health examinations among citizens [5]. We also included prescription data for systemic an-
Received: June 19, 2017
Revision received: August 22, 2017 Accepted: October 27, 2017 Corresponding author: Hyukmin Lee
Department of Laboratory Medicine and Research Institute of Bacterial Resistance, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Korea
Tel: +82-2-2019-3530, Fax: +82-2-2057-8926 E-mail: [email protected]
© Korean Society for Laboratory Medicine.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Kim YA, et al.
Antibiotic cycling for P. aeruginosa
https://doi.org/10.3343/alm.2018.38.2.176 www.annlabmed.org 177
tibiotics based on the Anatomical Therapeutic Chemical Classi- fication System in this study. Amount of use was standardized by Daily Defined Dose (DDD) and expressed as DDD per 1,000 inhabitants daily. Gentamicin and amikacin-resistance rates of P.
aeruginosa isolated from Korean general hospitals were obtained from the Korean Antimicrobial Resistance Monitoring System [6]. This study was approved by the Institutional Review Board of the National Health Insurance Service Ilsan Hospital (NHIMC 2017-03-026). We analyzed the data using SAS software version 9.2 (SAS Institute, Cary, NC, USA). The relationship between antibiotic use and resistance was evaluated by simple correla- tion analysis. The significance level was set at P <0.05.
Despite the worsening resistance rates in other antibiotic classes in Korea [6], aminoglycosides might be the only ones showing decreasing trends of consumption and resistance rates. National gentamicin and total aminoglycoside consumption has continu- ously decreased and shown strong correlations with gentamicin- resistance rate of P. aeruginosa isolated from general hospitals with more than 100 beds (Fig. 1).
National amikacin consumption has continuously decreased after 2006. Amikacin-resistance rate of P. aeruginosa in the same year did not correlate with amikacin usage. However, it showed strong correlation at two-year intervals (Fig. 2).
The reason for this difference is currently unclear, but we sus- pected it to be due to different gentamicin- and amikacin- resis- tance mechanisms. Gentamicin resistance is mediated mainly by aminoglycoside modification, but 16S rRNA methyltransfer- ase production constitutes a high level of resistance to amino- glycoside, especially to amikacin [7].
Other researchers reported that restriction of gentamicin and tobramycin decreased the resistance rate to both antimicrobials
especially in P. aeruginosa in the 1980s [8, 9]. The study was performed during the period of introduction of amikacin and emergence of plasmid-mediated resistance to gentamicin. In Korea, Ku et al [3] reported that decreasing prevalence of ami- kacin and tobramycin resistance in P. aeruginosa isolates were associated with decreased consumption levels of these antimi- crobials; but this correlation was not observed with gentamicin.
This was discordant with our study and that of Lai et al [10], which showed good correlation with gentamicin and amikacin. The study by Ku et al [3] was a single center analysis from 2001 to 2011, and could be affected by patients’ characteristics, infec- tion control policy, and microbiological factors.
The strength of this study is that it is based on nationwide sur- veillance and antibiotic prescription database spanning an ex- tended period; thus the findings are representative of the popu- lation. This study suggests that less aminoglycoside consump- tion correlates with less resistance levels, hence the need for an antibiotic cycling strategy at the national level.
Authors’ Disclosure of Potential Conflicts of Interest
We have nothing to declare.
Acknowledgment
This study was supported by a grant (2016-20-001) from the National Health Insurance Service Ilsan Hospital. This study ac- Fig. 1. Correlation of national aminoglycoside usage and gentami-
cin-resistance rates (%) of P. aeruginosa (GEN-R-PAE) isolated from general hospitals. Correlation of gentamicin usage and GEN-R-PAE (correlation coefficient r=0.83, P =0.0028); correlation of total ami- noglycoside usage and GEN-R-PAE (r=0.92, P =0.0001).
45 40 35 30 25 20 15 10 5 0
1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013
Year
Resistance rate (%) DDD per 1,000 inhabitants daily
Gentamicin-resistance rates (%) of Pseudomonas aeruginosa National aminoglycoside usage
National gentamicin usage
Fig. 2. Correlation of national amikacin usage and amikacin-resis- tance rates (%) of P. aeruginosa (AMK-R-PAE) isolated from gener- al hospitals. Correlation of amikacin usage and AMK-R-PAE in the same year (correlation coefficient r=–0.11, P =0.8192); correlation of amikacin usage and AMK-R-PAE with 2-year interval (r =0.77, P =0.0145).
Amikacin-resistance rates (%) of Pseudomonas aeruginosa
Amikacin-resistance rates (%) of Pseudomonas aeruginosa (2 years after) National amikacin usage
30 25 20 15 10 5 0
0.09 0.08 0.07 0.06 0.05 0.04 0.03 0.02 0.01 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 0
Year
Resistance rate (%) DDD per 1,000 inhabitants daily
Kim YA, et al.
Antibiotic cycling for P. aeruginosa
178 www.annlabmed.org https://doi.org/10.3343/alm.2018.38.2.176 quired permission for using NHIS-NSC (REQ0000007609).
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